Lack of association of the cholesterol 24-hydroxylase (CYP46) intron 2 polymorphism with Alzheimer’s disease

An association was recently reported between an increased risk of Alzheimer’s disease and an intron 2 AA genotype of CYP46, the enzyme hydroxylating cholesterol to 24S-hydroxycholesterol. Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-β and tau in brain and cerebrospinal...

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Bibliographic Details
Published in:Neuroscience letters 2004-09, Vol.367 (2), p.228-231
Main Authors: Ingelsson, Martin, Jesneck, Jennifer, Irizarry, Michael C., Hyman, Bradley T., Rebeck, G.William
Format: Article
Language:English
Subjects:
Aged
Alleles
Alzheimer Disease - genetics
Amyloid
Amyloid beta-Peptides - metabolism
APOE
Apolipoprotein E4
Apolipoproteins E - genetics
Biological and medical sciences
Cholesterol 24-Hydroxylase
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Efflux
Enzyme-Linked Immunosorbent Assay - methods
Female
Fundamental and applied biological sciences. Psychology
Genetics
Genotype
Humans
Immunohistochemistry - methods
Introns - genetics
Lipoprotein
LXR
Male
Medical sciences
Middle Aged
Neocortex - metabolism
Neocortex - pathology
Neurofibrillary Tangles - metabolism
Neurology
Neuropathology
Peptide Fragments - metabolism
Polymorphism, Genetic - genetics
Postmortem Changes
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Messenger - biosynthesis
Steroid Hydroxylases - genetics
Vertebrates: nervous system and sense organs
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Summary:An association was recently reported between an increased risk of Alzheimer’s disease and an intron 2 AA genotype of CYP46, the enzyme hydroxylating cholesterol to 24S-hydroxycholesterol. Moreover, CYP46 AA-carriers were found to have increased levels of amyloid-β and tau in brain and cerebrospinal fluid. We determined the CYP46 intron 2 genotype in a cohort of 178 AD and 105 non-demented control subjects, but found no significant association with AD for any of the individual genotypes or alleles. Further, in an autopsy confirmed subset of this cohort, the proposed CYP46 risk genotype was not associated with any increase in the brain levels of amyloid-β40, amyloid-β42 or in the levels of amyloid plaques and neurofibrillary tangles. Despite growing evidence implicating cholesterol metabolism in AD risk and Aβ generation, our data does not support a robust genetic relationship between the CYP46 intron 2 polymorphism and AD risk or neuropathology.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2004.06.011